Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA.
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA; Graduate Field of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853, USA.
Cell Rep. 2019 Oct 1;29(1):76-88.e7. doi: 10.1016/j.celrep.2019.08.076.
Efforts to target glutamine metabolism for cancer therapy have focused on the glutaminase isozyme GLS. The importance of the other isozyme, GLS2, in cancer has remained unclear, and it has been described as a tumor suppressor in some contexts. Here, we report that GLS2 is upregulated and essential in luminal-subtype breast tumors, which account for >70% of breast cancer incidence. We show that GLS2 expression is elevated by GATA3 in luminal-subtype cells but suppressed by promoter methylation in basal-subtype cells. Although luminal breast cancers resist GLS-selective inhibitors, we find that they can be targeted with a dual-GLS/GLS2 inhibitor. These results establish a critical role for GLS2 in mammary tumorigenesis and advance our understanding of how to target glutamine metabolism in cancer.
为癌症治疗靶向谷氨酰胺代谢的努力集中在谷氨酰胺酶同工酶 GLS 上。同工酶 GLS2 在癌症中的重要性仍不清楚，在某些情况下被描述为肿瘤抑制因子。在这里，我们报告 GLS2 在占乳腺癌发病率>70%的腔型肿瘤中上调并必不可少。我们表明，GATA3 在腔型细胞中上调 GLS2 的表达，而启动子甲基化在基底型细胞中抑制 GLS2 的表达。尽管腔型乳腺癌对 GLS 选择性抑制剂有抗性，但我们发现它们可以用双重 GLS/GLS2 抑制剂靶向。这些结果确立了 GLS2 在乳腺肿瘤发生中的关键作用，并加深了我们对如何靶向癌症中谷氨酰胺代谢的理解。
